scholarly journals Nanobodies Enhancing Cancer Visualization, Diagnosis and Therapeutics

2021 ◽  
Vol 22 (18) ◽  
pp. 9778
Author(s):  
Dhaneshree Bestinee Naidoo ◽  
Anil Amichund Chuturgoon
Keyword(s):  
Patient Outcomes ◽  
Half Life ◽  
Cancer Imaging ◽  
Health Concern ◽  
Antigen Binding ◽  
Imaging Diagnosis ◽  
Treatment Practices ◽  
Tumor Penetration ◽  
Incidence And Mortality ◽  
High Immunogenicity

Worldwide, cancer is a serious health concern due to the increasing rates of incidence and mortality. Conventional cancer imaging, diagnosis and treatment practices continue to substantially contribute to the fight against cancer. However, these practices do have some risks, adverse effects and limitations, which can affect patient outcomes. Although antibodies have been developed, successfully used and proven beneficial in various oncology practices, the use of antibodies also comes with certain challenges and limitations (large in size, poor tumor penetration, high immunogenicity and a long half-life). Therefore, it is vital to develop new ways to visualize, diagnose and treat cancer. Nanobodies are novel antigen-binding fragments that possess many advantageous properties (small in size, low immunogenicity and a short half-life). Thus, the use of nanobodies in cancer practices may overcome the challenges experienced with using traditional antibodies. In this review, we discuss (1) the challenges with antibody usage and the superior qualities of nanobodies; (2) the use of antibodies and nanobodies in cancer imaging, diagnosis, drug delivery and therapy (surgery, radiotherapy, chemotherapy and immunotherapy); and (3) the potential improvements in oncology practices due to the use of nanobodies as compared to antibodies.

Abstract 034: Characterization of A Novel Maternally Restricted Pro-angiogenic Therapeutic for Preeclampsia

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
William H Stewart ◽  
Eric George ◽  
Gene L Bidwell ◽  
Heather Chapman ◽  
Fakhri Mahdi ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Half Life ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Chronic Administration ◽  
Health Concern ◽  
Pathogenic Factors ◽  
Clearance Kinetics

Background: Preeclampsia is a major obstetrical health concern, affecting 5-8% of all pregnancies. Hallmarked by hypertension and endothelial dysfunction the origin of the disease remains obscure, though it is generally accepted that placental insufficiency/ischemia is a central cause. In response, the placenta secretes pathogenic factors, in particular the anti-angiogenic protein sFlt-1. Currently, there is no effective therapy for the management of the preeclampsia patient. We have recently produced a novel synthetic peptide based on placental growth factor (PlGF) which is maternally restricted by fusion to the synthetic carrier elastin like polypeptide (ELP). Here, we describe its in vivo pharmacokinetics and biodistribution. Methods: Fluorescently labeled ELP-PLGF was administered i.v. and blood sampled serially to determine clearance kinetics. Long-term pharmacokinetics and biodistribution was performed after subcutaneous administration of labeled peptide. Measurements were made on serially drawn blood, and in the whole animal by in vivo imaging. Results: ELP-PlGF exhibited markedly more favorable pharmacokinetics than the normal half life of PlGF, with a terminal half-life of ~10 hours as opposed to ~30 minutes for PlGF alone. Chronic administration found highest levels accumulating in placenta and kidney (two favorable targets for preeclampsia) and liver. A single subcutaneous administration at 100mg/kg resulted in sustained therapeutic plasma concentrations for over 10 days. Conclusion: These data demonstrate that ELP-PlGF has favorable pharmacokinetic and biodistribution profiles. Previous data suggest ELP-PlGF directly antagonizes sFlt-1 in culture. Future studies to assess the in vivo effectiveness of ELP-PlGF in managing placental ischemia induced hypertension and endothelial dysfunction are currently in progress. Acknowledgment: This work was supported by NIH grants R0121527 (GLB), T32HL105324 (OCL), P01HL51971, P20GM104357 (EMG), and R00HL116774 (EMG)

scholarly journals Radiation-induced lung toxicity – cellular and molecular mechanisms of pathogenesis, management, and literature review

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Lukas Käsmann ◽  
Alexander Dietrich ◽  
Claudia A. Staab-Weijnitz ◽  
Farkhad Manapov ◽  
Jürgen Behr ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Patient Outcomes ◽  
Lung Fibrosis ◽  
Major Part ◽  
Molecular Mechanisms ◽  
Limiting Factors ◽  
Incidence And Mortality ◽  
High Incidence ◽  
Radiation Induced

Abstract Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on radiotherapy as a major part of multi-modality care, and treatment-related toxicities, such as radiation-induced pneumonitis and/or lung fibrosis, are important dose limiting factors with direct impact on patient outcomes and quality of life. In this review, we summarize the current understanding of radiation-induced pneumonitis and pulmonary fibrosis, present predictive factors as well as recent diagnostic and therapeutic advances. Novel candidates for molecularly targeted approaches to prevent and/or treat radiation-induced pneumonitis and pulmonary fibrosis are discussed.

scholarly journals Epidemiology and risk factors for pyogenic liver abscess in the Calgary Health Zone revisited: a population-based study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jennifer A. Losie ◽  
John C. Lam ◽  
Daniel B. Gregson ◽  
Michael D. Parkins
Keyword(s):  
Risk Factors ◽  
Incidence Rate ◽  
Liver Abscess ◽  
Census Data ◽  
Pyogenic Liver Abscess ◽  
Analysis Data ◽  
Mortality Rates ◽  
Health Concern ◽  
Incidence And Mortality ◽  
Health Zone

Abstract Background Pyogenic liver abscess (PLA), although uncommon in North America, is associated with significant morbidity and mortality. We sought to re-examine the epidemiology, risk factors, and outcomes of PLA in a large, diverse Canadian health zone. Methods All Calgary Health Zone (CHZ) residents aged ≥20 with PLA between 2015 and 2017 were identified. Incidence and mortality rates were calculated using census data. Risk factors for PLA were identified using a multivariate analysis. Data was compared to 1999–2003 data, also collected in the CHZ. Results There were 136 patients diagnosed with PLA between 2015 and 2017. Incidence rate during this period increased significantly relative to 1999–2003 (3.7 vs 2.3 cases/100,000 population, p < 0.01), however, mortality rates remained similar. The microbiological composition of PLA did not change over this 15-year time period but the number of antimicrobial resistant isolates did increase (8% vs 1%, p = 0.04). The greatest risk factors for PLA relative to general populations included current malignancy, liver-transplant, end-stage renal disease, and cirrhosis. Thirty-day mortality was 7.4% and independent risk factors included polymicrobial bacteremia, absence of abscess drainage, congestive-heart failure, a history of liver disease, and admission bilirubin. Conclusions Pyogenic liver abscess is a health concern with rising incidence rate. The increasing prevalence of comorbidities in our population and factors that are associated with risk of PLA suggests this will continue to be an emerging diagnosis of concern. Increasing prevalence of antibiotic resistant organisms compounding unclear optimal treatment regimens is an issue that requires urgent study.

Stiffness of targeted layer-by-layer nanoparticles impacts elimination half-life, tumor accumulation, and tumor penetration

2021 ◽  
Vol 118 (42) ◽  
pp. e2104826118
Author(s):  
Stephanie M. Kong ◽  
Daniel F. Costa ◽  
Anna Jagielska ◽  
Krystyn J. Van Vliet ◽  
Paula T. Hammond
Keyword(s):  
Drug Delivery ◽  
Half Life ◽  
Tumor Targeting ◽  
Layer By Layer ◽  
Elimination Half Life ◽  
Tumor Penetration ◽  
Anticancer Drug Delivery ◽  
Elimination Half ◽  
Tumor Accumulation

Nanoparticle (NP) stiffness has been shown to significantly impact circulation time and biodistribution in anticancer drug delivery. In particular, the relationship between particle stiffness and tumor accumulation and penetration in vivo is an important phenomenon to consider in optimizing NP-mediated tumor delivery. Layer-by-layer (LbL) NPs represent a promising class of multifunctional nanoscale drug delivery carriers. However, there has been no demonstration of the versatility of LbL systems in coating systems with different stiffnesses, and little is known about the potential role of LbL NP stiffness in modulating in vivo particle trafficking, although NP modulus has been recently studied for its impact on pharmacokinetics. LbL nanotechnology enables NPs to be functionalized with uniform coatings possessing molecular tumor-targeting properties, independent of the NP core stiffness. Here, we report that the stiffness of LbL NPs is directly influenced by the mechanical properties of its underlying liposomal core, enabling the modulation and optimization of LbL NP stiffness while preserving LbL NP outer layer tumor-targeting and stealth properties. We demonstrate that the stiffness of LbL NPs has a direct impact on NP pharmacokinetics, organ and tumor accumulation, and tumor penetration—with compliant LbL NPs having longer elimination half-life, higher tumor accumulation, and higher tumor penetration. Our findings underscore the importance of NP stiffness as a design parameter in enhancing the delivery of LbL NP formulations.

scholarly journals Programmed Death Ligand 1: A Poor Prognostic Marker in Endometrial Carcinoma

Diagnostics ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 394
Author(s):  
Mianxin Chew ◽  
Yin Ping Wong ◽  
Norain Karim ◽  
Muaatamarulain Mustangin ◽  
Nurwardah Alfian ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Immune Cells ◽  
Immune Cell ◽  
Tumour Cells ◽  
Health Concern ◽  
Major Health ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Incidence And Mortality ◽  
Gynaecologic Malignancy

Endometrial carcinoma is the only gynaecologic malignancy with a raising incidence and mortality, posing a major health concern worldwide. The upregulation of programmed death ligand 1 (PD-L1) on tumour cells causes T-cell suppression, which impedes antitumour immunity, promotes immune cell evasion and enhances tumour survival. The aim of this study was to evaluate PD-L1 expression in endometrial carcinoma and to correlate it with survival rate. A total of 59 cases of endometrial carcinoma were evaluated. Thirty-two cases of non-neoplastic endometrial tissue were included as control. PD-L1 immunohistochemistry was performed on all cases. PD-L1 expression was evaluated on tumour cells and immune cells. PD-L1 was positive in 62.7% (37/59) and 28.8% (17/59) of immune cells and tumour cells, respectively. PD-L1 expression in immune cells was significantly higher in endometrial carcinoma than in non-neoplastic endometrium (p < 0.001). Among the patients with endometrial carcinoma, PD-L1 expression in tumour cells was significantly higher in patients who died (10/15, 66.7%) compared to those who survived (7/44, 15.9%) (p < 0.001). It is noteworthy to point out that the expression of PD-L1 in tumour cells was significantly associated with a poor survival. This suggests that immunomodulation using PD-L1 inhibitors may be useful in advanced endometrial carcinoma.

scholarly journals Development of Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer: An Update

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 934
Author(s):  
Bryan D. Fleming ◽  
Mitchell Ho
Keyword(s):  
Liver Cancer ◽  
Half Life ◽  
Potential Role ◽  
Cancer Therapeutics ◽  
Bacterial Toxin ◽  
T Cell Epitopes ◽  
Cancer Treatments ◽  
Liver Cancers ◽  
Global Demand ◽  
High Immunogenicity

Hepatocellular carcinoma (HCC) accounts for most liver cancers and represents one of the deadliest cancers in the world. Despite the global demand for liver cancer treatments, there remain few options available. The U.S. Food and Drug Administration (FDA) recently approved Lumoxiti, a CD22-targeting immunotoxin, as a treatment for patients with hairy cell leukemia. This approval helps to demonstrate the potential role that immunotoxins can play in the cancer therapeutics pipeline. However, concerns have been raised about the use of immunotoxins, including their high immunogenicity and short half-life, in particular for treating solid tumors such as liver cancer. This review provides an overview of recent efforts to develop a glypican-3 (GPC3) targeting immunotoxin for treating HCC, including strategies to deimmunize immunotoxins by removing B- or T-cell epitopes on the bacterial toxin and to improve the serum half-life of immunotoxins by incorporating an albumin binding domain.

scholarly journals Tumor-Shed Antigen Affects Antibody Tumor Targeting: Comparison of Two 89Zr-Labeled Antibodies Directed against Shed or Nonshed Antigens

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Jae-Ho Lee ◽  
Heejung Kim ◽  
Zhengsheng Yao ◽  
Lawrence P. Szajek ◽  
Luigi Grasso ◽  
...  
Keyword(s):  
Half Life ◽  
Tumor Targeting ◽  
High Dose ◽  
Distribution Profile ◽  
Tumor Penetration ◽  
Lewis Y Antigen ◽  
Tumor Periphery ◽  
Ideal System ◽  
Dose Dependent ◽  
Higher Doses

We investigated the effect of shed antigen mesothelin on the tumor uptake of amatuximab, a therapeutic anti-mesothelin mAb clinically tested in mesothelioma patients. The B3 mAb targeting a nonshed antigen was also analyzed for comparison. The mouse model implanted with A431/H9 tumor, which expresses both shed mesothelin and nonshed Lewis-Y antigen, provided an ideal system to compare the biodistribution and PET imaging profiles of the two mAbs. Our study demonstrated that the tumor and organ uptakes of 89Zr-B3 were dose-independent when 3 doses, 2, 15, and 60 μg B3, were compared at 24 h after injection. In contrast, tumor and organ uptakes of 89Zr-amatuximab were dose-dependent, whereby a high dose (60 μg) was needed to achieve tumor targeting comparable to the low dose (2 μg) of 89Zr-B3, suggesting that shed mesothelin may affect amatuximab tumor targeting as well as serum half-life. The autoradiography analysis showed that the distribution of 89Zr-B3 was nonuniform with the radioactivity primarily localized at the tumor periphery independent of the B3 dose. However, the autoradiography analysis for 89Zr-amatuximab showed dose-dependent distribution profiles of the radiolabel; at 10 μg dose, the radiolabel penetrated toward the tumor core with its activity comparable to that at the tumor periphery, whereas at 60 μg dose, the distribution profile became similar to those of 89Zr-B3. These results suggest that shed antigen in blood may act as a decoy requiring higher doses of mAb to improve serum half-life as well as tumor targeting. Systemic mAb concentration should be at a severalfold molar excess to the shed Ag in blood to overcome the hepatic processing of mAb-Ag complexes. On the other hand, mAb concentration should remain lower than the shed Ag concentration in the tumor ECS to maximize tumor penetration by passing binding site barriers.

Precision Medicine: Update on Diagnosis and Therapeutic Strategies of Hepatocellular Carcinoma

2018 ◽  
Vol 25 (17) ◽  
pp. 1999-2008 ◽  
Author(s):  
Qing Liang ◽  
Xiaoying Shen ◽  
Guangchun Sun
Keyword(s):  
Hepatocellular Carcinoma ◽  
Precision Medicine ◽  
Massively Parallel Sequencing ◽  
Therapeutic Strategies ◽  
Detection Methods ◽  
Health Concern ◽  
Tumor Evolution ◽  
High Risk Population ◽  
Significant Heterogeneity ◽  
Incidence And Mortality

Recent advances in multiple omics technologies and the advent of massively parallel sequencing provide technical supports for the implementation of precision medicine. The precision medicine emphasizes that heterogeneous diseases can be well classified into more precise subtypes by the powerful detection methods and integration of clinical features, so that the clinicians should develop more accurate diagnosis and therapeutic strategies for the disease subtype population in an effort to maximize the efficacy and minimize the unnecessary side effects. Oncology is at the forefront of precision medicine, as malignant tumors have significant heterogeneity and are among the leading causes of death nationally and worldwide. The incidence and mortality of Hepatocellular Carcinoma (HCC), a kind of extraordinarily heterogeneous malignancy, have been increasing worldwide, making it a major public health concern. Such heterogeneity affects key signaling pathways, driving phenotypic variation, influences tumor evolution, and poses severe challenges to HCC treatment. The application of precision medicine will have certain impact on HCC diagnosis and treatment strategies. Herein, we summarize the updates and challenges in high-risk population screening, prevention, diagnosis, staging and therapy of HCC under the concept of precision medicine.

scholarly journals Activated TAZ Induces Liver Cancer in Collaboration with EGFR/HER2 Signaling Pathways

2021 ◽  
Author(s):  
Hyuk Moon ◽  
Hye Jin Choi ◽  
Do Young Kim ◽  
Simon Weonsang Ro
Keyword(s):  
Liver Cancer ◽  
Signaling Pathways ◽  
Primary Liver Cancer ◽  
Active Form ◽  
Health Concern ◽  
Liver Carcinogenesis ◽  
Regulator Protein ◽  
Incidence And Mortality ◽  
Her2 Signaling ◽  
Immunohistochemical Analyses

Abstract Liver cancer is a major global health concern due to the steady increases in its incidence and mortality. Transcription factors, yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, also known as TAZ)have emerged as critical regulators in human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), the two major types of primary liver cancer. However, our study as well as other previous reports have shown that activation of YAP and TAZ (YAP/TAZ) in adult murine livers is insufficient for the development of liver cancer, suggesting a requirement for an additional oncogenic collaborator for liver carcinogenesis in adulthood. Therefore,we sought to identifythe oncogenic partners of YAP/TAZ that promote hepatocarcinogenesis in adults. Through database analyses, we identified EGFR/HER2signaling to be essential in human cancerswith high TAZ activity.Furthermore,immunohistochemical analyses showedthat human HCC and CC tissues with high YAP/TAZ activities exhibited concomitant activation of EGFR/HER2downstream signaling pathways. To demonstrate that EGFR/HER2 signaling promotes YAP/TAZ-mediated hepatocarcinogenesis, a constitutively active form of TAZ was simultaneously expressed in murine adult livers with effector molecules downstream of EGFR/HER2 signaling pathways.Interestingly, activated TAZ and BRAFinduced HCC, whereas activated TAZ and PI3K led to the development of CC-like cancer, demonstrating that TAZ collaborates with EGFR/HER2 signaling pathways to induce both HCC and CC.

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